Over the past several decades, the frequency of antimicrobial resistance and its association with serious infectious diseases have increased at alarming rates. The increasing prevalence of resistance among nosocomial pathogens is particularly disconcerting. Of the over 2 million nosocomial infections occurring each year in the United States, 50 to 60% are caused by antimicrobial-resistant strains of bacteria. The high rate of resistance to commonly used antibacterial agents increases the morbidity, mortality, and costs associated with nosocomial infections. In the United States, nosocomial infections are thought to contribute to or cause more than 77,000 deaths per year and cost approximately $5 to $10 billion annually.
Among the most important antibiotics currently available are several classes of compounds that contain a beta-lactam ring, including penicillins, penems, carbapenems, cephalosporins, monobactams and sulfactams. These beta-lactam antibiotics inhibit cell wall biosynthesis by binding to proteins called penicillin-binding proteins (PBPs), which are essential for synthesis of peptidoglycan, the major component of the cell wall of Gram-negative and Gram-positive bacteria. While beta-lactam antibiotics remain extremely important worldwide, their extensive use has led to a large and growing problem: bacteria have developed resistance to beta-lactams, just as they have to most other available antibiotics. Indeed, the World Health Organization (WHO) says antibiotic resistance is a “serious, worldwide threat . . . .”
Several different mechanisms of resistance to beta-lactam antibiotics have been identified: some resistant strains possess efflux pumps to excrete antibiotic, and others develop mutant PBPs that are less sensitive to the antibiotic. An especially troubling form of resistance is development of bacterial enzymes that react with these antibiotics, destroying the antibiotic by opening the beta-lactam ring. These antibiotic-degrading enzymes are called beta-lactamases, and are particularly problematic because they can impart resistance to many different beta-lactam antibiotics, and they can be transferred via plasmids between different bacterial strains and species. Among Gram-negative bacteria, there are four classes of beta-lactamases, the serine beta-lactamases of the classes A, C and D, and the metallo beta-lactamases (class B).
Important causes of resistance to beta-lactam antibiotics include extended-spectrum beta-lactamases (ESBLs), serine carbapenemases of the class A, (e.g. KPC-2) and of class D (e.g. OXA-48) in Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis, as well as high-level resistance against third-generation cephalosporins mediated by the class C beta-lactamase AmpC among Enterobacter species and Citrobacter freundii, and multidrug-resistance strains of Pseudomonas, Acinetobacter, and Stenotrophomonas. The problem of antibacterial resistance is compounded by the existence of bacterial strains containing multiple beta-lactamases. For example, Klebsiella pneumonia harboring NDM-1 metallo-beta-lactamase frequently carries additional serine-beta-lactamases on the same plasmid that carries the NDM-1.
Since beta-lactam antibiotics are among the few classes that are effective against Gram-negative bacteria, many efforts have been made to bolster their ability to control resistant bacterial strains, in order to avoid losing these enormously valuable antibacterials. For example, some beta-lactams have been modified structurally to make them less susceptible to beta-lactamases, although this approach is complicated by the fact that there are already many different beta-lactamases, and new ones arise constantly. Another approach has been to inhibit the beta-lactamase enzymes that degrade these antibiotics by using a small-molecule beta-lactamase inhibitor (BLI) in combination with a beta-lactam antibiotic. These BLIs can be used in combination with an approved beta-lactam antibiotic to treat patients infected with bacteria that are resistant to the antibiotic alone due to beta-lactamase activity. Examples of approved BLIs include clavulanic acid, sulbactam, tazobactam, and avibactam. Others (relebactam, vaborbactam (RPX7009), zidebactam, and nacubactam) are reportedly in development.
In Gram-positive organisms, penicillin resistance mediated by penicillinase-type beta-lactamases is an important mechanism of resistance in Staphylococcus aureus (MSSA). Beta-lactamase-mediate resistance to penicillins is also found in anaerobic species, like bacteroides.
The three most commonly used serine beta-lactamase inhibitors, clavulanic acid, tazobactam and sulbactam, have potent activity only against some class A beta-lactamases, excluding serine carbapenemases. Avibactam is a member of the diazabicyclooctane (DBO) class of beta-lactamase inhibitors and has a broad coverage of class A (including KPCs), class C and some inhibition of class D. Along with beta-lactamase inhibition, avibactam also has antibacterial activity against some clinical strains through inhibiting penicillin binding protein 2 (PBP-2) (Asli et al, Antimicrobial Agents and Chemotherapy, 60, No 2, 752, 2016). Antibacterial compounds with this mechanism of action, including DBOs, select for resistance at very high frequencies in vitro (Doumith et al, J. Antimicrobial Chemotherapy 2016, 71, 2810-2814). Because of this, any potential clinical benefit of the intrinsic antibacterial activity of some DBO beta-lactamase inhibitors is currently unclear. The weak antibacterial activity of avibactam may not be clinically relevant, since the clinical dose of avibactam is fairly low, however, it may complicate in vitro susceptibility testing and/or promote resistance. In vitro susceptibility testing of avibactam/beta-lactam combinations against clinical isolates is typically conducted using a high fixed concentration of avibactam (4 μg/mL) that likely does not reflect the clinically achieved levels. The direct contribution of avibactam to antibacterial activity under these artificial in vitro testing conditions could affect the accuracy in predicting clinical efficacy of avibactam/beta-lactamase combinations. A DBO beta-lactamase inhibitor devoid of significant antibacterial activity would not have this extra confounding activity, and in vitro testing protocols would measure only the reversal of beta-lactamase mediated resistance in clinical isolates, enabling a more accurate prediction of clinical efficacy based on in vitro susceptibility results.
In addition to BLIs currently available for use, other compounds with BLI activity are disclosed in WO2002/100860, US2003/0199541, US2004/0157826, WO2008/039420, and WO2009/091856, US2010092443, WO2010/126820, WO2013/122888, WO2013/038330, US2013/0225554, WO2013149121, WO2013149136, WO2014141132 and WO2014/033560.
The pharmacokinetic and physical properties of previously described BLIs may not be ideal for use with every beta-lactam antibiotic. Moreover, known BLIs are reportedly losing effectiveness over time (K. Bush, Int. J. Antimicrob. Agents 46(5), 483-93 (November 2015)), as resistant bacterial strains develop and new beta-lactamase enzymes arise continually. Accordingly, there remains a need for new beta-lactamase inhibitors to extend the usefulness of valuable beta-lactam antibiotics; indeed, novel BLIs may also combat resistance to known BLIs as well as resistance to known and future-developed beta-lactam antibiotics. The present invention provides novel beta-lactamase inhibitors that potentiate the activity of various beta-lactam antibiotics, while they exhibit little intrinsic (direct) antibiotic activity of their own.